Glaucoma is the occurrence of elevated intraocular pressure which causes progressive blindness in the form of gradual loss of peripheral fields of vision. It is an important cause of blindness and occurs in 1-2% of individuals over the age of 60. Often the disease is asymptomatic, as the patient painlessly and gradually loses vision. Before a diagnosis is made, the patient may have lost half of the one million optic nerve fibers in one eye. Today, intervention is focused on early detection, which depends on a routine eye examination which includes intraocular pressure measurement (tonometry), funduscropy with attention to the optic disc appearance, and visual field testing. In the normal eye, the optic cups are symmetric and the neural rim is pink. In glaucoma, either localized notching or generalized enlargement of the optic cup can be seen. The rim, although thinned, remains pink until late in the disease. The central optic cup diameter can be compared with the diameter of the disc. The ratio of the horizontal and vertical dimensions can be recorded. The normal cup-disc ratio is less than 0.2 to 0.3. Vertical disparity in one or both eyes is an early sign of glaucoma.
Glaucoma is often asymmetric. The finding of asymmetry of the cup-disc ratio implies glaucoma. Early in the disease, visual field loss may include nonspecific constriction and small paracentral scotomas. Eventually, the arcuate nerve fiber bundle defects develop with a characteristic nasal step: The arcuate bundle defect extends to the nasal horizontal raphe to form a step-like configuration on kinetic visual field testing. The papillomacular bundle and vision are spared until late in the disease (HARRISON'S PRINCIPLES OF INTERNAL MEDICINE, 13.sup.th ed. Ed. By Isselbacher, Braunwald, Wilson, Martin, Fauci and Kasper. McGraw-Hill, New York City, 1996. Pp. 104-6). Intraocular pressure reflects the balance between the production and outflow of aqueous humor. The normal range for measurements by applanation tonometry (the tonometer applanates the corneal surface) is 2.09.+-.2.5 mmHg. Another method of measuring intraocular pressure is briefly indenting the cornea with a Schiotz tonometer.
Glaucoma has a number of different etiologies. Glaucoma results from decreased outflow of fluid from the aqueous humor, the gel which occupies the intraocular space. The fluid does not properly drain through the pupil, trabecular meshwork, and Schlemm's canal and intraocular pressure rises. Open-angle or chronic glaucoma is the most common in adults. It is asymptomatic and only observed on a routine eye exam. There is a relative obstruction of the trabecular network of unknown cause. Treatment involves controlling intraocular pressure with topical agents including cholinergic (pilocarpine, carbachol, echothiophate) or adrenergic agonists (epinephrine dipivefrin) or antagonists such as .beta.-adrenergic blockers including timolol, levobunalol and betaxolol. If topical agents do not reduce the intraocular pressure sufficiently, systemic carbonic anhydrase inhibitors such as acetazolamide or methazolamine are added. If medical therapy fails, surgery is tried, such as laser trabeculoplasty or filtration surgery, to improve aqueous outflow.
Open-angle or secondary glaucoma may occur in patients with ocular inflammatory or neoplastic disease, with mature cataracts. It also can occur with long-term topical or systemic glucocorticoid therapy.
Another form of glaucoma is called angle-closure glaucoma, which occurs when the iris blocks egress of aqueous humor through the trabecular meshwork. There is a primary form in which abnormal anatomy of the eye block drainage of the fluid through the pupil and the trabecular meshwork. The intraocular pressure rises suddenly whenever the pupil dilates. Symptoms include severe eye and face pain, nausea, vomiting, colored halos around lights, and loss of vision. Common signs are hyperemia, corneal edema and a fixed mid-dilated pupil. The intraocular pressure must be reduced urgently and is accomplished with hyperosmotic agents, including oral glycerin and sorbitol or intravenous mannitol. Acute angle-closure glaucoma is often treated with laser or surgical iridotomy.
Secondary angle-closure glaucoma occurs when the lens or ciliary body becomes swollen, pushing the iris against the trabecular meshwork or sealing the iris to the trabecular meshwork as a result of the formation of a neovascular network. This may occur in patients with diabetic retinopathy, advanced ocular ischemic syndrome due to severe occlusive carotid disease or inflammatory adhesions (synechiae) which can occur after iritis.
Compression of the optic nerve causes insidious progressive vision loss and visual field loss. The disc may be normal, swollen or atrophic. Intrinsic tumors which may compress the optic nerve include optic nerve sheath meningioma and glioma. In Graves' ophthalmopathy, optic neuropathy is due to compression of the nerve in the orbital apex by the enlarged extraocular muscles. Benign or malignant orbital tumors, metastatic lesions, tumors arising from the adjacent paranasal sinuses and middle cranial fossa and giant pituitary adenomas can each lead to compressive optic neuropathy.
Vision may be lost if papilledema is not promptly treated. Papilledema is swelling of the optic nerve head due to increased intracranial pressure. It is usually bilateral and occurs with brain tumors and abscesses, cerebral trauma and hemorrhage, meningitis, arachnoidal adhesions, pseudotumor cerebri, cavernous sinus thrombosis, dural sinus thrombosis, encephalitis, space-occupying brain lesions, severe hypertensive disease and pulmonary emphysema.
Vision also can be lost due to higher visual pathway lesions. The retinal nerves gather into the optic nerve, which may be impinged on in its pathway to the optic chiasma. At the optic chiasma the optic nerve fibers from the medial halves of both retina cross to the opposite side before connecting to the occipital visual cortex. Lesions at the optic chiasma tend to cause bilateral vision loss. Lesions at the visual cortex cause vision loss in the portions of the two retinas which are on the same side as the cortical lesion. Thus, vision is vulnerable to a number of different pathologies in a variety of intracranial locations.
Even if the patient obtains appropriate treatment, treatment today is limited to stopping further progression of vision loss, not improving vision. Because the patient may have already lost so much peripheral vision that he is effectively blind, the patient may not be permitted to drive, which may cause loss of job and independence, resulting in important deterioration in productivity and quality of life. A method of restoring at least some of the vision to enable the patient to return to work and other activities is sorely needed.
Because glaucoma and related conditions represent loss of central nervous neurons, it is appropriate to consider animal models of the treatment of central nerve damage, such as the neurotoxic Huntington's Disease (HD) model and the middle cerebral artery (MCA) stroke model.
Neural transplantation has been tried as a therapy in several animal models of Parkinson's disease and other neurodegenerative disorders (Bjorklund and Stenevi, Brain Res. 177:555-60, 1979; Sanberg et al., CELL TRANSPLANTATION FOR HUNTINGTON'S DISEASE, R. G. Landes Company, Austin Tex., 1994, p 124). This experimental treatment has been applied clinically in Parkinson's disease (PD) with favorable results (Lindvall et al., Science 247:574-77, 1990; Kordower et al., New Engl. J. Med. 332:1118-24, 1995; Freeman et al., Ann. Neurol. 38:379-88, 1995). Recently preliminary clinical trials of neural transplantation in HD also were conducted (Kurth et al., Amer. Soc. Neurol. Transplant. Abstr. 3:15, 1996). Previous studies on animal models of HD using neurotoxins (Sanberg et al., Prog. Brain Res. 82: 427-431, 1990; Borlongan et al., Brain Res. 697:254-57, 1995a; Borlongan et al., Brain Res. Bull. 36:549-56, 1995b) revealed selective lesions in the striatum, the brain area implicated in HD. Subsequent transplantation of neural cells in these neurotoxic HD models led to anatomical and behavioral recovery (Isacson et al., Neuroscience 22:481-97, 1987; Wictorin et al., Neuroscience 37:301-15, 1990; Borlongan et al., Restorative Neurol. Neurosci. 9:15-19, 1995c; and Pundt et al., Brain Res. Bull. 39:23-32, 1996).
Because of the similar brain damage in neurotoxic HD models and the MCA model, same-species fetal neural transplantation has been tested in ischemia (Nishino et al. 1993, ibid.; Koide et al., Restorative Neurol. Neurosci. 5:205-14, 1993; and Aihara et al., Brain Res. Bull. 33:483-88, 1993). Nishino et al. disclosed the effects of fetal rat striatal cell transplants in ischemic rats on a passive avoidance learning and memory task. Control animals acquired this task with minimal training, while ischemic animals had a marked and persistent impairment in acquiring this task. If ischemic rats received fetal striatal cell transplants two weeks after their surgery, the rats partially improved the ischemia-induced deficit in passive avoidance behavior. This improvement was observed at one month and extended throughout the three-month post-transplant test period. While these preliminary results are encouraging, they need to be replicated, and cognitive and locomotor alterations need to be evaluated. In general, rat fetal striatal cells grafted into the ischemic rat striatum significantly alleviated the chemical and behavioral deficits (See Borlongan et al., Neurosci. Biohav. Rev. 21:79-90, 1997). These results suggest that fetal neural transplantation may be beneficial in treating transient, focal cerebral ischemia.
However, logistical and ethical problems hinder widespread use of human fetal issue for human neural transplantation (Borlongan et al., Neurolog. Res. 18:297-304, 1996b). Alternative graft sources have been explored, such as encapsulated cells and genetically engineered cells (Emerich et al., 1996, ibid.; Kawaja et al., J. Neurosci. 12:2849-64, 1992). However, there is a need to develop cell lines that generate large numbers of differentiated or post-mitotic cells for human transplantation therapies (Mantione et al., Brain Res. Bull. 671:33-337, 1995). Recently we have transplanted treated cultured human neuronal cells (NT-2-Neuron cells derived from an embryonal cell line isolated from a human teratocarcinoma (Ntera2 or NT-2/D1.TM. cells) into the rodent brain (Kleppner et al., J. Comp. Neurol. 357:618-32, 1995; Miyazono et al., Brain Pathol. 4:575, 1994; Trojanowski et al., Exp. Neurol. 122:283-94, 1993). After retinoic acid treatment, NT-2/D1 cells differentiated into post-mitotic neuron-like (hNT-Neuron.TM.) cells (Pleasure et al., J. Neurosci. Res. 35:585-602, 1992). In vivo studies indicate that transplanted hNT-Neuron cells can survive, mature and integrate into host brain (Kleppner et al., 1995, ibid.; Mantione et al., 1995, ibid.; Trojanowski et al., 1993, ibid.). Transplanted rats have been observed for more than one year, during which none of the transplanted hNT-Neuron cells have reverted to a neoplastic state.
These features of human hNT-Neuron cells, coupled with the localized lesion of certain types of vision losses, provided the basis for investigating the effects of hNT-Neuron cell transplantation on vision loss.